![[dr. bob]](/dr-bob-sm.gif)
Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.orgShown: posts 1 to 25 of 25. This is the beginning of the thread.
Posted by alesta on August 22, 2004, at 8:23:36
fjfj
Posted by linkadge on August 22, 2004, at 8:28:43
In reply to are stimulants neurotoxic? thanks in advance. (NM), posted by alesta on August 22, 2004, at 8:23:36
I think that stimulants are probablt not neurotoxic when used in proper doses. I think neurotoxicity comes in to play when they are used recreationally to cause massive increases in cerebral metabolism
Linkadge
Posted by Ame Sans Vie on August 22, 2004, at 10:52:43
In reply to Re: are stimulants neurotoxic? thanks in advance., posted by linkadge on August 22, 2004, at 8:28:43
I agree with linkadge. Stimulants (amphetamines in particular) have a wonderful history of safety that spans more than seventy years. But this is only true when used judiciously, at lower doses than, for example, those used in studies on rats to determine amphetamine toxicity. These studies generally will use upwards of 10mg/kg *by injection* (and often directly into specific areas of the brain that oral amphetamine administration doesn't even affect) to demonstrate neurotoxicity when the average therapeutic daily dose of dextroamphetamine in humans (regardless of age) is generally in the 0.05 to 2mg per kilogram range, *orally*.
I'd certainly be more concerned with cardiovascular detriment associated with use of psychostimulants (or, in the case of magnesium pemoline, hepatotoxicity). But cardio problems in relatively healthy individuals are few, and can, in the majority of instances, be resolved by a switch of medication, reduced dosage, or antihypertensive/antiarrhythmic drugs if absolutely necessary. For what it's worth, my research on the subject has led me to believe that methylphenidate (Ritalin, Concerta, Methylin, Metadate) is associated with a higher occurrence of cardio side effects than amphetamine or dextroamphetamine, with methamphetamine posing the least risk of all.
~Michael
Posted by alesta on August 22, 2004, at 11:20:34
In reply to Re: are stimulants neurotoxic? thanks in advance., posted by Ame Sans Vie on August 22, 2004, at 10:52:43
hi, ame!
thank you! good to see you again!
considering the cardio strain involved, wouldn't it be better for people to take provigil instead, as it is different from the other stimulants in that it doesn't produce the typical negative side effects of stimulants? and strattera for adhd, since it isn't a stimulant at all? thanks....
amy:)
Posted by zeugma on August 22, 2004, at 13:39:04
In reply to Re: are stimulants neurotoxic? thanks in advance., posted by alesta on August 22, 2004, at 11:20:34
> hi, ame!
>
> thank you! good to see you again!
>
> considering the cardio strain involved, wouldn't it be better for people to take provigil instead, as it is different from the other stimulants in that it doesn't produce the typical negative side effects of stimulants? and strattera for adhd, since it isn't a stimulant at all? thanks....
>
> amy:)
>
>
hi amy, i want to note that I was on Strattera for a year, and yes, it was very helpful for a time. But the drug is more complex than advertised, as in fact most drugs tend to be. I experienced an anhedonic, anergic depression, which is unusual for me in that while I am normally pretty anergic (my caffeine intake is MASSIVE and that's just to stay awake) anhedonia is not something I've experienced often, although I am certainly not someone who has accumalted a massive amount of 'hedons' as J.S Mill would call them, as would be expected of someone who's suffered from nearly lifelong depression.Anyway, I believe the cause for Strattera's nasty side effects has been discovered:
Bioorg Med Chem Lett. 2004 Aug 2;14(15):4083-5. Related Articles, Links
Synthesis and biological evaluation of the major metabolite of atomoxetine: elucidation of a partial kappa-opioid agonist effect.Creighton CJ, Ramabadran K, Ciccone PE, Liu J, Orsini MJ, Reitz AB.
Drug Discovery, Johnson and Johnson Pharmaceutical, Research and Development, Spring House, PA 19477-0776, USA. ccreight@prdus.jnj.com
The major human metabolite of atomoxetine (4-hydroxyatomoxetine) was tested against a panel of receptors and enzymes, and was found to interact with the mu, delta, and kappa-opioid receptors based upon studies involving both binding and functional assays. 4-hydroxyatomoxetine was determined to be a partial agonist of the kappa-opioid receptor.
The opioid activity of this metabolite, which the manufacturer claims circulates at only 1 percent of the concentration of the parent drug, is probably responsible for the numerous reports of fatigue, unwanted sedation, and just plain depression that have surfaced about this drug. It is substantially less protein bound than the parent, and it is estimated to circulate in plasma at approximately equal concentrations to atomoxetine itself, in normal metabolizers of the drug.
I have read the leading psychopharmacologists of the world (Dr. Stahl and company) debate this sedating effect, in the absence of this newly surfaced data, and they specualte that it must be a 'paradoxical' effect surfacing from stimulation of alpha-1 or alpha-2 receptors. This explanation was one I immediately distrusted, because reboxetine which is quite similar to atomoxetine tends to produce complaints about overstimulation, not fatigue, and desipramine which is also quite similar to atomoxetine generally is also on the stimulating end of the spectrum (though not of course a stimulant).
Provigil is a reasonably effective drug (for me at least) but its benefits were counteracted by its half-life, which is longer than that of the other stims, and which caused a major insomnia problem for me. I wish I could have taken it, because I am at risk for cardio complications due to the TCA I take, and I require a stimulant of some kind besides just caffeine. So I'm on a tiny dose of Ritalin LA, and trying to make the best of it.
-z
Posted by JayDee on August 22, 2004, at 19:51:28
In reply to are stimulants neurotoxic? thanks in advance. (NM), posted by alesta on August 22, 2004, at 8:23:36
The stims may not be neurotoxic but, according to this http://www.prozactruth.com/ritalinarticle.htm (too much?) Dopamine is.
Another reason to leave the Stims only to the people who have low Dopamine levels to begin with.(PS - Ame, did you get my BabbleMail?)
Jon
Posted by alesta on August 23, 2004, at 8:12:52
In reply to Re: are stimulants neurotoxic? thanks in advance., posted by Ame Sans Vie on August 22, 2004, at 10:52:43
hi, michael :),
i didn't feel i thanked you sufficiently for your most informative and helpful response, rather than simply bombarding you with more questions:). thanks for taking the time to share your valuable insight on this issue, as i have had a very hard time finding good info on this issue on the internet.
appreciatively,
amy
Posted by alesta on August 23, 2004, at 8:27:02
In reply to Re: are stimulants neurotoxic? thanks in advance. » alesta, posted by zeugma on August 22, 2004, at 13:39:04
hello, zeugma! :)
how are you doing today?:) always nice to hear from you! thank you so much for letting me know that about the strattera...veeeeddy interesting....:)!
and i didn't know about provigil's long half-life. that does definitely seem potentially problematic for sure, as far as sleep is concerned. and i'm sure you'll do just fine on the ritalin.:)
take care!
amy
>
> Provigil is a reasonably effective drug (for me at least) but its benefits were counteracted by its half-life, which is longer than that of the other stims, and which caused a major insomnia problem for me. I wish I could have taken it, because I am at risk for cardio complications due to the TCA I take, and I require a stimulant of some kind besides just caffeine. So I'm on a tiny dose of Ritalin LA, and trying to make the best of it.
>
> -z
>
>
>
Posted by alesta on August 23, 2004, at 8:34:58
In reply to Re: are stimulants neurotoxic? thanks in advance., posted by JayDee on August 22, 2004, at 19:51:28
hi, jon :),
this info appears to coming from a radical, anti-drug website, so i don't know how much validity we can place on their claims. but that is interesting....i wonder if this is bs or a real danger....thanks for posting that! :)
amy :)
> The stims may not be neurotoxic but, according to this http://www.prozactruth.com/ritalinarticle.htm (too much?) Dopamine is.
> Another reason to leave the Stims only to the people who have low Dopamine levels to begin with.
>
> (PS - Ame, did you get my BabbleMail?)
>
> Jon
Posted by JayDee on August 23, 2004, at 17:50:38
In reply to Re: are stimulants neurotoxic? thanks in adv--jon, posted by alesta on August 23, 2004, at 8:34:58
Amy, yes that appears the be the case! But if you read closely in that article and others he recognizes the necessity for medication in many situations. And in that particular article is about Protecting the Brain from the 'neurotoxic' effects of Ritalim(dopamine) rather then discouraging it's use. Also there appears to be refrences in the article to credable past research...
Then again it could just be a promotion of (his?) antioxidant product.
Jon
Posted by zeugma on August 23, 2004, at 18:41:06
In reply to Re: are stimulants neurotoxic? thanks in --zeugma, posted by alesta on August 23, 2004, at 8:27:02
hi amy, nice to hear from you too...:)hmm, it's been a busy couple of days, my p/t job did not give me much rest, but now that I have a couple of minutes to settle down and play some good music and reply to your post... it's been up and down, i had a bout of insomnia (i mean up till 5 am) on thursday night i think, then had to be at work early; as usual it made me feel really bad later on, during the weekend (is the weekend really over? oh yes it's monday). I've been doing better than i did earlier in the year with another episode of all-night insomnia, where by the end of the week i was having a very unpleasant feeling of unraveling completely at work. i was so out of it that i was walking into stationary objects, and it was nothing so benign as a tree or a pole... some folks on the bus were pretty irate with me!
Anyway, about the neurotoxicity of stims, I have seen good info that neither methylphenidate nor the pharmacologically similar cocaine are neurotoxic. In fact methylphenidate may be 'neuroprotective', in some sense of that possibly overused word. The prozactruth-derived info is in my opinion, and ironically, false. One need not sing the praises of Eli Lilly to conclude that a site devoted to its evils is not the last word when it comes to pharmacology.
I have also been struck by reports that modafinil (Provigil) is neuroprotective, and I decided to try 50 mg Provigil with 10 mg Ritalin LA this morning. It's the cardio effects from Ritalin that concern me, more than anything else, and testing the hypothesis that small doses of related but distinct drugs might have a synergy beyond what either, suboptimally dosed, might be expected to deliver spurred me on, particularly since I still don't feel all the way 'there' yet. It was very calming, good for my concentration, and when unexpected demands were placed on me at work, it was not too taxing. I had the usual Provigil feeling of being slightly sick to my stomach, and that was a s/e that was even worse at 100 mg, so 50 mg may be all I can handle anyway. I am concerned about insomnia, but I have to see what happens; feeling chronically underaroused is no fun either. Plus, I was becoming tolerant of the pediatric dose of Ritalin, and I think my pdoc is (rightly) concerned about possible cardio complications and interactions with nortriptyline. I will discuss the matter with him soon. It is proving difficult for me to get reliable info about how methylphenidate influences TCA metabolism. Modafinil seems much more benign in this regard.
-z
Posted by Shawn. T. on August 24, 2004, at 5:41:59
In reply to Re: are stimulants neurotoxic? thanks in --zeugma » alesta, posted by zeugma on August 23, 2004, at 18:41:06
Dopamine- induced neurotoxicity is primarily a result of the oxidation of free intracellular dopamine. Ritalin prevents dopamine reuptake, an effect that has been associated with a significant reduction in dopamine neurotoxicity. Less reuptake results in less intracellular dopamine. In addition, Ritalin increases vesicular dopamine uptake; this causes an even greater decrease in free intracellular dopamine. If these arguments aren't convincing enough, see the first article below; even multiple 120mg/kg doses of Ritalin weren't enough to produce a long-term depletion of striatal DA axonal markers in mice. I think that the author of the site had good intentions; he just didn't know what he was talking about in this instance.
Shawn
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=9365033
Posted by alesta on August 24, 2004, at 8:14:25
In reply to Re: are stimulants neurotoxic? thanks in adv--jon, posted by JayDee on August 23, 2004, at 17:50:38
hi, again, jon,:)
ok, here's my input:
i trust what the national institute on drug abuse, national institutes of health has to say. and all they are saying is that ritalin increases dopamine. so that's fine.
where they go from there with this info is a huge, illogical leap right into saying that dopamine causes neuronal cell death. it makes no sense how they came to this conclusion from the above. and then they cite a few people as references. no cigar, baby. they're gonna have to do a lot better than that...
in addition, they don't elaborate on *anything*. and they don't explain how an *essential neurotransmitter* is toxic (they don't even say at elevated levels), when everyone obviously has dopamine in their brain! i guess we're all poisoned from birth...
hope this might put your mind at ease...i try to steer clear of this website whenever possible..
take care,
amy :)
Posted by alesta on August 24, 2004, at 8:59:47
In reply to Re: are stimulants neurotoxic? thanks in --zeugma » alesta, posted by zeugma on August 23, 2004, at 18:41:06
hi, zeug :),
i'm sorry to hear about your insomnia. i know how destructive sleep deprivation can be.
> "i was so out of it that i was walking into stationary objects, and it was nothing so benign as a tree or a pole... some folks on the bus were pretty irate with me!"
that's hilarious! sorry...:)what about that new drug, ambien? i'm sure you've probably already tried it, though....
> "I decided to try 50 mg Provigil with 10 mg Ritalin LA this morning."
that sounds like a *great* idea...i'm sure you probably already do this, but i would take the provigil the moment you get up in the morning so that it will wear off sooner, hopefully by bedtime. (it would be nice if it even elicited a bit of a crash for you so you could sleep.)
i wanted to add that i have no more fears whatsoever as to the neurotoxicity of stims. i believe now that the likelihood of stims being neurotoxic is the equivalent of the likelihood for antidepressants, antipsychotics, etc. so i am not worried one bit.:)
au revoir!
amy :)> hi amy, nice to hear from you too...:)hmm, it's been a busy couple of days, my p/t job did not give me much rest, but now that I have a couple of minutes to settle down and play some good music and reply to your post... it's been up and down, i had a bout of insomnia (i mean up till 5 am) on thursday night i think, then had to be at work early; as usual it made me feel really bad later on, during the weekend (is the weekend really over? oh yes it's monday). I've been doing better than i did earlier in the year with another episode of all-night insomnia, where by the end of the week i was having a very unpleasant feeling of unraveling completely at work. i was so out of it that i was walking into stationary objects, and it was nothing so benign as a tree or a pole... some folks on the bus were pretty irate with me!
>
> Anyway, about the neurotoxicity of stims, I have seen good info that neither methylphenidate nor the pharmacologically similar cocaine are neurotoxic. In fact methylphenidate may be 'neuroprotective', in some sense of that possibly overused word. The prozactruth-derived info is in my opinion, and ironically, false. One need not sing the praises of Eli Lilly to conclude that a site devoted to its evils is not the last word when it comes to pharmacology.
>
> I have also been struck by reports that modafinil (Provigil) is neuroprotective, and I decided to try 50 mg Provigil with 10 mg Ritalin LA this morning. It's the cardio effects from Ritalin that concern me, more than anything else, and testing the hypothesis that small doses of related but distinct drugs might have a synergy beyond what either, suboptimally dosed, might be expected to deliver spurred me on, particularly since I still don't feel all the way 'there' yet. It was very calming, good for my concentration, and when unexpected demands were placed on me at work, it was not too taxing. I had the usual Provigil feeling of being slightly sick to my stomach, and that was a s/e that was even worse at 100 mg, so 50 mg may be all I can handle anyway. I am concerned about insomnia, but I have to see what happens; feeling chronically underaroused is no fun either. Plus, I was becoming tolerant of the pediatric dose of Ritalin, and I think my pdoc is (rightly) concerned about possible cardio complications and interactions with nortriptyline. I will discuss the matter with him soon. It is proving difficult for me to get reliable info about how methylphenidate influences TCA metabolism. Modafinil seems much more benign in this regard.
>
> -z
Posted by alesta on August 24, 2004, at 9:04:45
In reply to Re: is Ritalin neurotoxic?, posted by Shawn. T. on August 24, 2004, at 5:41:59
thank you for that very informative info, shawn!:)
amy :)
Posted by alesta on August 24, 2004, at 10:24:14
In reply to Re: is Ritalin neurotoxic?, posted by Shawn. T. on August 24, 2004, at 5:41:59
hello.
please look at this hyperlink:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=9365033
so, great, ritalin is in the clear. but now i'm wondering about the amphetamines. does this study indicate that amphetamines are neurotoxic? or is this another study where they *injected* the rats with *super-high* doses in their brains? any help would be vastly appreciated. i feel this info could potentially help people.....
luv you,
amy> Dopamine- induced neurotoxicity is primarily a result of the oxidation of free intracellular dopamine. Ritalin prevents dopamine reuptake, an effect that has been associated with a significant reduction in dopamine neurotoxicity. Less reuptake results in less intracellular dopamine. In addition, Ritalin increases vesicular dopamine uptake; this causes an even greater decrease in free intracellular dopamine. If these arguments aren't convincing enough, see the first article below; even multiple 120mg/kg doses of Ritalin weren't enough to produce a long-term depletion of striatal DA axonal markers in mice. I think that the author of the site had good intentions; he just didn't know what he was talking about in this instance.
>
> Shawn
>
> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=9365033
>
> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15198987
>
> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12604695
Posted by Dave001 on August 24, 2004, at 17:29:02
In reply to Re: is Ritalin neurotoxic?, posted by Shawn. T. on August 24, 2004, at 5:41:59
> Dopamine- induced neurotoxicity is primarily a result of the oxidation of free intracellular dopamine.
While there is little doubt that increased levels of ROS are present in many (most?) degenerative diseases, I'm curious how you arrived at this conclusion. Could you please elaborate on the process immediately preceding the oxidation of the free intracellular dopamine that you propose, leading up to the damage of DA neurons?
Also, how would you explain that animals with depletions of brain DA appear equally vulnerable to the neurotoxicity of amphetamines? [1,2]
Dave
1. Albers DS and Sonsalla PK (1995) Methamphetamine-induced hyperthermia and dopaminergic neurotoxicity in mice: Pharmacological profile of protective and nonprotective agents. J Pharmacol Exp Ther 275: 1104-1114
2. Wagner GC, Lucot JB, Schuster CR and Seiden LS (1983) Alpha-Methyltyrosine attenuates and reserpine increases methamphetamine-induced neuronal changes. Brain Res 270: 285
<snip>
Posted by alesta on August 24, 2004, at 19:58:31
In reply to AME or somebody please help....again!!!!, posted by alesta on August 24, 2004, at 10:24:14
after looking at the study, and looking up proper dosages (i'm not familiar with/don't take stimulants), these are definitely extremely high dosages, injected or not. so the question remains, does this study, which shows neurotoxicity resulting from amphetamines at high doses, prove neurotoxicity at lower doses, especially considering the contrast with the results concerning ritalin?
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=9365033
Posted by Dave001 on August 24, 2004, at 19:58:37
In reply to AME or somebody please help....again!!!!, posted by alesta on August 24, 2004, at 10:24:14
> hello.
>
> please look at this hyperlink:
>
> http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=9365033
>
> so, great, ritalin is in the clear. but now i'm wondering about the amphetamines. does this study indicate that amphetamines are neurotoxic? or is this another study where they *injected* the rats with *super-high* doses in their brains? any help would be vastly appreciated. i feel this info could potentially help people.....I posted that abstract the other day. One thing the authors are saying here is that the release of dopamine alone isn't enough to explain the neuronal damage mediated by the amphetamines.
One thing to keep in mind about doses is that they can't be scaled directly (as a proportion of bodyweight) from one species to another. They first have to be adjusted for body surface area. According to the chart I have, when scaling the doses from mice to humans, you would first divide the dose by 12.3. You would divide by 7.4 for hamsters, 6.2 for rats, and 1.8 for dogs. These figures assume a 60 kg human. However, the formula I have that is supposed to be reasonably accurate for most scenarios is the following:
Human equivalent dose = animal dose in mg/kg x (animal weight in kg/human weight in kg) ^0.33*So when you see a dose of say, 10 mg/kg fed to rats, that would correspond to an approximate dose of 49 mg (gee, I think we can say 50) in a human of 60 kg or 132 lb.
* Since I can't use superscripts in text-only presentation, the ^ character is used to indicate exponentiation.
Dave
<snip>
Posted by alesta on August 24, 2004, at 20:35:19
In reply to Re: AME or somebody please help....again!!!! » alesta, posted by Dave001 on August 24, 2004, at 19:58:37
Hi, dave!:)
Do you realize that we posted at almost exactly the same time??? strange...:)
Thanks for replying! I wonder how you know this stuff...do you have a medical background?
So, are you saying that you do think amphetamines (i'm not talking all stimulants here, people, just amphetamines) are neurotoxic? they did have a more damaging impact than the ritalin, although at UNGODLY HIGH DOSES, like you expressed. the normal dose for a human being per day is .05-2 mg, and they said they used from 10-120 mg/kg for the rats! your scaling of 10 mg to the human equivalent was bad enough. i can't imagine what the equivalent of 120 mg would be for a human!
thanks for that informative info! i always enjoy your input.:)
Amy....:)
Posted by Dave001 on August 24, 2004, at 22:19:16
In reply to dave, posted by alesta on August 24, 2004, at 20:35:19
>day is .05-2 mg, and they said they used from 10-120 mg/kg for the rats! your scaling of 10 mg to the human equivalent was bad enough. i can't imagine what the equivalent of 120 mg would be for a human!
>Maybe I was not clear in my last post. When I said 10 mg/kg fed to rats would correspond to an approximate dose of 50 mg for a 60 kg human, I meant 50 mg *total*, not 50 mg/kg.
Oops! I messed up... I meant to say mice, not rats. 10 mg/kg in mice would equal about 50 mg total for a 60 kg human; 10 mg/kg fed to rats would be about equal to 100 mg total in humans.
The message is still the same though: the *relative* dose equivalent on a mg/kg basis is higher for rodents than humans. That is, 12.3 mg/kg for a mouse is equal to 1 mg/kg in a human, which is equal to 6.2 mg/kg in rats, etc. So you can see that these rodents can tolerate much higher doses than humans based on weight.
Dave
Posted by Shawn. T. on August 24, 2004, at 22:44:13
In reply to Re: is Ritalin neurotoxic? » Shawn. T., posted by Dave001 on August 24, 2004, at 17:29:02
I apologize; I thought that I had included an article by Jones et al. (2000) in that list of abstracts (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=10820189). They found that nomifensene, a dopamine reuptake inhibitor, prevented dopamine- induced apoptosis in 60-70% of PC12 cells. The cells were incubated with a relatively large (300 microM) amount of dopamine; I speculate that nomifensene would have prevented apoptosis in a larger percentage of cells if a lower concentration of dopamine had been added to the medium. The assumption is that most of the dopamine added would enter the cell via the dopamine transporter; if nomifensene had not protected a majority of the cells from apoptosis, then we could have assumed that extracellular dopamine was playing the more important role.
I should have said that dopamine- induced neurotoxicity is primarily a result of processes involving free intracellular dopamine. The oxidation of dopamine could be the primary causal factor in some but not all cases of dopamine- induced neurotoxicity. For example, Rochet et. al (2004) recently found that a reaction between dopamine and alpha-synuclein could play a key role in the degeneration of dopamine neurons in Parkinson's disease (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15126689). Peter Jenner (2003) has argued that it is not possible to separate the roles of oxidative stress and other events involved in dopaminergic cell death (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12666096). However, I assume that in the future, more will be known about the possible sequences of events that can lead to dopamine- induced neurotoxicity.
Johnson-Davis et al. (2004) found that methamphetamine pretreatment attenuates the decrease in function of the vesicular monoamine transporter-2 (VMAT-2) as well as the persistent dopamine deficits that are induced by the drug (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14747615). Guilarte et al. (2003) have suggested that "Brain regions exhibiting DAT and 5-HTT deficits that co-localize with decreased VMAT-2 levels and glial cell activation may represent monoaminergic terminal degeneration" (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14614914). If tolerance to the effects of methamphetamine on VMAT-2 actually does reduce the neurotoxic effects of the drug, then the addition of a drug that can further decrease VMAT-2 activity would be expected to increase toxicity. Reserpine is a vesicular monoamine transporter inhibitor, so the two articles that you cited add further support to the hypothesis that VMAT-2 inhibition is involved in methamphetamine- induced neurotoxicity. Resperine prevents the transfer of monoamines into storage vesicles; this inhibits the exocytotic release of dopamine, but it does not deplete intracellular dopamine. See Mosharov et al. (2003) for a discussion of the effects of reserpine on cytosolic levels of catecholamines and catechols in cultured chromaffin cells (http://www.jneurosci.org/cgi/content/full/23/13/5835).
Thanks for pointing out the misstatement.
Shawn
Posted by alesta on August 25, 2004, at 10:25:26
In reply to Re: is Ritalin neurotoxic? » Dave001, posted by Shawn. T. on August 24, 2004, at 22:44:13
i am still unclear as to whether this study really proves anything (concerning amphetamine neurotoxicity). it proves that at amazingly high doses, amphetamines are more toxic than ritalin. but does this prove that amphetamines are neurotoxic at normal doses, or is it impossible to really conclude from this study?
amy :)
Posted by Dave001 on August 25, 2004, at 15:55:52
In reply to are amphet. neurotoxic?i am still unclear on this, posted by alesta on August 25, 2004, at 10:25:26
> i am still unclear as to whether this study really proves anything (concerning amphetamine neurotoxicity). it proves that at amazingly high doses, amphetamines are more toxic than ritalin. but does this prove that amphetamines are neurotoxic at normal doses, or is it impossible to really conclude from this study?
>Nobody knows the answer to that. It probably depends on a lot of factors besides just dose. Probably age is a large factor. Young animals have much more efficient natural antioxidant defense mechanisms, for example. Tolerance is also another major factor. Unless the dose is continually increased, tolerance would attenuate much of the potential neurotoxicity.
FWIW, I think that in most of the rat studies there was a "no harm" threshold somewhere around 20 mg/kg, which would be close to 3 mg/kg in a human. Then again, rats also metabolize the stuff a lot faster us, so who knows how the timing of the doses scale to humans. Again, nobody knows.
Dave
Posted by alesta on August 25, 2004, at 16:53:32
In reply to Re: are amphet. neurotoxic?i am still unclear on t, posted by Dave001 on August 25, 2004, at 15:55:52
thanks, dave. i guess we can put this thread to rest now. i appreciate your time. :)have a nice evening. :)
take care,
amy :)
This is the end of the thread.
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